Osteoarthritis (arthrosis) is a degenerative joint disease which affects most people from 65 years of age, and which is characterized by a gradual degradation of cartilaginous tissue, combined with the presence of inflammation and pain. Synovial inflammation normally occurs later, when the disease is in an advanced state, and generally, it is only a secondary component in osteoarthritic pathology.
Osteoarthritis can be defined as the degeneration of hyaline articular cartilage. A secondary effect thereto is the damage of the synovial membrane and the subchondral bone (the bone in contact with the cartilage), as well as the formation of new bone at the margins of the surfaces of the joint.
Cartilage allows bones to move sliding over one another. It also absorbs the tension caused by the physical movement. In osteoarthritis, the cartilage surface breaks and wears away, causing the bones to move against one another, causing friction, pain, swelling and loss of movement in the joint. As time goes on the joint can be deformed.
In normal conditions, cartilage renewal is a very slow process consisting of a constant synthesis (anabolism) and degradation (catabolism) of the components of the extracellular matrix. The chondrocyte is the cell responsible for this metabolism, a process which must be perfectly coordinated.
Although the etiology of osteoarthritis is still not known, it is currently accepted as true that the first alterations occur at chondrocyte level, said alterations will subsequently give rise to the onset of an osteoarthritic joint.
A series of risk factors for the onset of the disease has been described, some of them include: aging, heredity, obesity, overload disorders, physical overtraining in sportsmen, injuries or traumas, work activity and low bone mineral density.
Osteoarthritis is a disease that does not have a definitive treatment. The following current therapeutic possibilities will be emphasized:
Fast acting symptomatic drugs. Among them are to be found: analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), corticoids and cyclooxygenase-2 (COX-2) selective inhibitors. The use of some of them involves a high risk of potentially serious side-effects, such as gastrointestinal problems in the case of NSAIDs.
Slow acting symptomatic drugs. They are known as SYSADOA (Symptomatic Slow Acting Drug for Osteoarthritis) (M. G. Lequesne, Rev. Rhum. (Eng./Ed.), 61, 69-73 (1994); B. F. Leeb et al., J. Rheumatol., 27, 205-211 (2000)). Some of these substances include: hyaluronic acid, chondroitin sulphate and glucosamine hydrochloride. This group is characterized by having an overall efficacy similar to NSAIDs and, furthermore, as additional advantages, a higher safety and a more prolonged action over time, even for some months after the suspension of the treatment (carry over effect). Some clinical trials carried out with hyaluronic acid (M. Dougados Semin. Arthritis. Rheum., 30(2 Suppl 1), 19-25 (2000)) and chondroitin sulphate (D. Uebelhart et al., Osteoarthritis Cart., 12, 269-276 (2004)) have shown the possibility that both compounds, in addition to acting as SYSADOA, can affect the course of the osteoarthritic disease, slowing down or delaying the disease such as S/DMOAD (Structure/Disease Modifying anti-Osteoarthritis Drug) drugs.
Ligaments and tendons are periarticular structures having a limited self-repairing capacity, especially in adult persons.
The functional and structural properties of tendons and of ligaments are very similar. Tendons are anatomical structures attaching muscles to bones and ligaments are similar structures attaching bones to other bones. Both are cylindrical, elongated structures, formed from dense connective tissue and adapted to tension in one direction, with parallel collagen (mainly type I collagen) fibres. The reduced vascularisation of said tissues is one of the causes of the slow healing of tendons and ligaments.
The predominant cells in tendons are called tenocytes. The function of tenocytes is to maintain the matrix structure through degradation and synthesis processes. However, the tendon has a relatively low cell density and with little mitotic activity, which explains the reduced rate of replacement of this tissue and questions the degree in which these cells can promote intrinsic healing.
Damages in tendons and ligaments are caused by different factors, including injuries due to practicing sports or accidents, distensions, incorrect postures, bacterial infections, adverse drug reactions, arthritis in a joint, and as a result of different diseases.
The healing below the optimal level, the long rehabilitation period and a high incidence of relapse make it difficult to suitably treat tendon and ligament injuries.
The most frequent pharmacological treatments for tendinopathies (tendon diseases) and desmopathies (ligament diseases) include the following: rest, physical therapy (exercises, massages, ultrasound, laser, hydrotherapy, heat and cold), dietary supplements, surgery and medicaments, including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids and antibiotics, the latter in the event that the disease has been caused by an infection. It is known that both NSAIDs and glucocorticoids have side-effects. Furthermore, recent publications question the efficacy of NSAIDs in tendon regeneration (D. Marsolais et al., “Nonsteroidal anti-inflammatory drug reduces neutrophil and macrophage accumulation but does not improve tendon regeneration”, Lab. Invest. 83(7), 991-999 (2003)).
In the last few years, investigations are being conducted on the treatment of tendinopathies and desmopathies with stem cells, tenocytes, ligament cells, growth factors or with genes.
The immune system disease called rheumatoid arthritis is a chronic and progressive inflammatory disorder, characterized by the onset of synovitis and a severe joint destruction.
The pathogenesis of rheumatoid arthritis is a complex process, involving cell proliferation and fibrosis at the synovial membrane level, the formation of pannus and cartilage and bone erosion. This process is mediated by interdependent network of cytokines, prostanoids and proteolytic enzymes.
The intermediate objectives in the treatment of rheumatoid arthritis are: controlling inflammatory symptoms, reducing pain, preventing or controlling the joint damage and preventing the loss of function, and the ultimate purpose of the treatment is to induce the complete remission of the disease, although this occurs infrequently.
Chondroitin sulphate is a natural sulphated glycosaminoglycan with a polymeric structure characterized by a disaccharide which is repeated, formed by N-acetyl-D-galactosamine and D-glucuronic acid. Most of the N-acetyl-D-galactosamine residues are sulphated. Chondroitin sulphate is an essential component of the aggrecan which is located in articular cartilage.
The use of chondroitin sulphate for treating different diseases, for example in the treatment of cardiovascular diseases (U.S. Pat. No. 3,895,106) or in the treatment of psoriasis (WO2005/014012), has been described, however, its most extended use is in the treatment of osteoarthritis (M. G. Lequesne, Rev. Rhum. Eng. Ed., 61, 69-73 (1994); G. Verbruggen et al., Osteoarthritis Cart., 6 (Supplement A), 37-38 (1998)), generally by means of the administration of 800-1,200 mg a day.
Contradictory results have been published on the use of chondroitin polysulphate in the treatment of tendinopathies. Although some authors describe its beneficial effect (H. Sundqvist et al., Int. J. Sports Med. 8, 298-303 (1987)), other authors, however, do not find significant differences between treated tendons and the control group (S. J. Dyson, Equine Vet. J. 36(5), 415-419 (2004)).
D-mannosamine (2-amino-2-deoxy-D-mannose) is an amino sugar the most extended use of which is in the synthesis of sialic acid and derivatives thereof, due to the fact that the physiological precursor of natural sialic acids is the N-acetylmannosamine. The use of N-acylmannosamines (N-acetyl, N-propanoyl, N-glycolyl, N-formylmannosamine) has also been described in the modulation of neuronal growth (WO 00/07602), and recently the use of N-acetylmannosamine for increasing the level of sexual hormones, particularly of testosterone (WO 2007/104576).
The amino sugar D-glucosamine (2-amino-2-deoxy-D-glucose) is an intermediate substrate used by articular cartilage in the synthesis of glycosaminoglycans and proteoglycans.
Several research groups have studied the effects of glucosamine hydrochloride in osteoarthritis (for example, H. Nakamura et al. Clin. Exp. Rheumatol. 22 (3), 293-9, (2004)).
There are documents in which compositions comprising chondroitin sulphate and amino sugars are described.
U.S. Pat. No. 5,587,363 describes a composition comprising chondroitin sulphate and glucosamine.
EP 1354590 claims an agent for treating articular disorders comprising an amino sugar and trehalose. The agent can comprise a glycosaminoglycan. Said document describes mixtures of chondroitin sulphate and glucosamine with and without trehalose, and also the combination of keratan sulphate, mannosamine and trehalose, as well as their activity in a type II collagen-induced arthritis model. The combination of chondroitin sulphate with mannosamine is neither described nor suggested in the document.
Due to the foregoing, the problem in which the present invention is based is that of providing an alternative treatment for osteoarthritis, periarticular diseases, in particular tendon or ligament diseases and immune system diseases, in particular rheumatoid arthritis.